Tissues lost as a consequence of periodontal disease, i.e., bone, cementum and a functional PDL, can be restored to some degree using existing periodontal therapies. Nevertheless, results are often disappointing and therefore, there is a need to develop new paradigms for regenerating periodontal tissues. Advanced technologies in cell transplantation and gene transfer enable us to ask critical questions as to the cellular and molecular mechanisms regulating periodontal cells both in vitro and in vivo. Answers to these questions will result in improved strategies for use in regenerating periodontal tissues. Based on studies to date we hypothesize that adenoviral constructs encoding either platelet-derived growth factor (PDGF) and/or bone morphogenetic protein-7 (BMP-7) transfected into cementoblasts and then incorporated into three dimensional biodegradable polymers for clinical application will improve outcomes of regenerative therapy. This hypothesis is supported by results indicating that: a) cultured cementoblasts express genes associated with comparable cells that promote cementum formation in situ, and that cultured cementoblasts induce mineral nodule formation within 7 days; b) PDGF and BMP-7 enhance periodontal cell function, in vitro and promote periodontal regeneration, in vivo; and c) biodegradable polymers allow for monitored release of factors to a local site and are compatible with wound healing, in vivo. This hypothesis will be tested under three specific aims: l) To determine transduction efficiency of adenoviral constructs, encoding BMP-7 and PDGF, into cementoblasts in vitro; 2) To establish the appropriate environment for promoting cementogenesis in vitro; and 3) To prove that cementoblasts regenerate cementum, in vivo and furthermore, that expression of PDGF and/or BMP-7 enhance regeneration. Knowledge gained from these studies will produce new insights into the use of gene therapy technologies to restore the periodontium as well as other mineral-associated tissues.